Tumor-associated nonmyelinating Schwann cell–expressed PVT1 promotes pancreatic cancer kynurenine pathway and tumor immune exclusion

• DOI: 10.1126/sciadv.add6995
• Publication Date: 2023-02-01T19:15:37Z
• Authors: Chengcao Sun; Youqiong Ye; Zhi Tan; Yuan Liu; Yajuan Li; Wei Hu; Ke Liang; Sergey D. Egranov; Lisa Angela Huang; Zhao Zhang; Yaohua Zhang; Jun Yao; Tina K. Nguyen; Zilong Zhao; Andrew Wu; Jeffrey R. Marks; Abigail S. Caudle; Aysegul A. Sahin; Jianjun Gao; Seth T. Gammon; David Piwnica-Worms; Jian Hu; Paul J. Chiao; Dihua Yu; Mien-Chie Hung; Michael A. Curran; George A. Calin; Haoqiang Ying; Leng Han; Chunru Lin; Liuqing Yang
• Keywords: 0301 basic medicine; Medical Sciences; Bioinformatics; 610; Cell Line; Biomedical Informatics; 03 medical and health sciences; Cell Line, Tumor; Medical Specialties; Medicine and Health Sciences; Tumor Microenvironment; Humans; Kynurenine; Cell Proliferation; Neoplastic; Tumor; Carcinoma; 3. Good health; Gene Expression Regulation, Neoplastic; Pancreatic Neoplasms; Gene Expression Regulation; Oncology; Pancreatic Ductal; RNA; Long Noncoding; RNA, Long Noncoding; Biomedicine and Life Sciences; Carcinoma, Pancreatic Ductal

One of the major obstacles to treating pancreatic ductal adenocarcinoma (PDAC) is its immunoresistant microenvironment. The functional importance and molecular mechanisms of Schwann cells in PDAC remains largely elusive. We characterized the gene signature of tumor-associated nonmyelinating Schwann cells (TASc) in PDAC and indicated that the abundance of TASc was correlated with immune suppressive tumor microenvironment and the unfavorable outcome of patients with PDAC. Depletion of pancreatic-specific TASc promoted the tumorigenesis of PDAC tumors. TASc-expressed long noncoding RNA (lncRNA) plasmacytoma variant translocation 1 ( PVT1 ) was triggered by the tumor cell–produced interleukin-6. Mechanistically, PVT1 modulated RAF proto-oncogene serine/threonine protein kinase–mediated phosphorylation of tryptophan 2,3-dioxygenase in TASc, facilitating its enzymatic activities in catalysis of tryptophan to kynurenine. Depletion of TASc-expressed PVT1 suppressed PDAC tumor growth. Furthermore, depletion of TASc using a small-molecule inhibitor effectively sensitized PDAC to immunotherapy, signifying the important roles of TASc in PDAC immune resistance.